Abstract
Topoisomerase IIα (Topo IIα), a well-conserved double-stranded DNA (dsDNA)-specific decatenase, processes dsDNA catenanes resulting from DNA replication during mitosis. Topo IIα defects lead to an accumulation of ultrafine anaphase bridges (UFBs), a type of chromosome non-disjunction. Topo IIα has been reported to resolve DNA anaphase threads, possibly accounting for the increase in UFB frequency upon Topo IIα inhibition. We hypothesized that the excess UFBs might also result, at least in part, from an impairment of the prevention of UFB formation by Topo IIα. We found that Topo IIα inhibition promotes UFB formation without affecting the global disappearance of UFBs during mitosis, but leads to an aberrant UFB resolution generating DNA damage within the next G1. Moreover, we demonstrated that Topo IIα inhibition promotes the formation of two types of UFBs depending on cell cycle phase. Topo IIα inhibition during S-phase compromises complete DNA replication, leading to the formation of UFB-containing unreplicated DNA, whereas Topo IIα inhibition during mitosis impedes DNA decatenation at metaphase–anaphase transition, leading to the formation of UFB-containing DNA catenanes. Thus, Topo IIα activity is essential to prevent UFB formation in a cell-cycle-dependent manner and to promote DNA damage-free resolution of UFBs.
Highlights
Genome stability requires accurate DNA replication during S-phase and correct chromosome segregation during mitosis
We reported that the intracellular accumulation of dCTP, due to cytidine deaminase (CDA) deficiency, leads to an excess of ultrafine anaphase bridges (UFBs)-containing unreplicated DNA, due to a decrease in the basal activity of poly(ADP-ribose) polymerase 1 (PARP-1), which promotes the premature entry of cells into mitosis, before the completion of DNA replication has been completed [16,19]
Topo IIα inhibition leads to a large increase in UFB frequency, and it has been proposed that Topo IIα activity is required for UFB resolution, accounting for the increase in UFB frequency upon Topo IIα inhibition [11,12,14,20,21,22]
Summary
Genome stability requires accurate DNA replication during S-phase and correct chromosome segregation during mitosis. Some dsDNA catenanes are not resolved before the onset of mitosis They form physical links between the sister chromatids and must be processed by Topo IIα before chromosome segregation in anaphase [9]. Topo IIα inhibition during S-phase impairs DNA replication, leading to the formation of UFB-containing unreplicated DNA during mitosis, whereas Topo IIα inhibition during mitosis prevents DNA decatenation, resulting in UFB-containing dsDNA catenanes. Topo IIα inhibition impairs both DNA replication during S-phase and DNA decatenation during mitosis, leading to the formation of two types of UFB with different molecular origins. Our results demonstrate that Topo IIα activity is required to prevent the formation of UFBs through replication defects or a lack of resolution of DNA catenanes when cells enter mitosis
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